Skip to main content

Advertisement

SpringerLink
Log in

Predicting liver cyst severity by mutations in patients with autosomal-dominant polycystic kidney disease

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Background

Most patients with autosomal-dominant polycystic kidney disease (ADPKD) develop liver cysts and polycystic liver disease as they age. To date, no simple clinical indicator has been confirmed to predict polycystic liver disease exacerbation. Furthermore, the effect of the type and location of mutation on disease progression of polycystic liver disease remains unclear. Here, we aimed to establish a simple liver cyst indicator for clinical practice and investigate whether gene mutations determined liver phenotype in patients with autosomal-dominant polycystic kidney disease.

Methods

In total, 129 patients with ADPKD were enrolled and liver cyst indicators were assessed based on mutation type (truncating mutation: nonsense, frameshift, and splicing mutation; non-truncating mutation: substitution) and mutation position. Liver cyst severity was determined using Gigot and Drenth classifications, based on their number, maximum diameter, and area ratio with the liver.

Results

We observed an overall prevalence of 62.8% for polycystic liver disease. Patients with PKD1 nonsense mutations, a type of PKD1 truncating mutation, exhibited more severe liver disease phenotypes than those without the mutation. We identified maximum diameter as a potential liver cyst indicator. Moreover, a subgroup analysis that included a PKD1 nonsense mutation cohort revealed that genetic mutations located closer to the 5ʹ end of PKD1 were associated with a maximum diameter index value ≥ 6 cm.

Conclusion

PKD1 nonsense mutations were associated with liver cyst severity, which along with maximum diameter index as a simple clinical indicator for liver cysts, may improve the treatment of polycystic liver disease associated with ADPKD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. van Aerts RMM, van de Laarschot LFM, Banales JM, Drenth JPH. Clinical management of polycystic liver disease. J Hepatol 2018;68:827–837

    Article  Google Scholar 

  2. Mochizuki T, Tsuchiya K, Nitta K. Autosomal dominant polycystic kidney disease: recent advances in pathogenesis and potential therapies. Clin Exp Nephrol 2013;17:317–326

    Article  CAS  Google Scholar 

  3. Masyuk TV, Masyuk AI, LaRusso NF. Polycystic liver disease: the interplay of genes causative for hepatic and renal cystogenesis. Hepatology 2018;67:2462–2464

    Article  Google Scholar 

  4. Zhang ZY, Wang ZM, Huang Y. Polycystic liver disease: classification, diagnosis, treatment process, and clinical management. World J Hepatol 2020;12:72–83

    Article  CAS  Google Scholar 

  5. Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 1996;272:1339–1342

    Article  CAS  Google Scholar 

  6. Fedeles SV, Tian X, Gallagher AR, Mitobe M, Nishio S, Lee SH, Cai Y, Geng L, Crews CM, Somlo S. A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat Genet 2011;43:639–647

    Article  CAS  Google Scholar 

  7. Lantinga MA, Gevers TJ, Drenth JP. Evaluation of hepatic cystic lesions. World J Gastroenterol. 2013;19:3543–54.

    Article  Google Scholar 

  8. Abu-Wasel B, Walsh C, Keough V, Molinari M. Pathophysiology, epidemiology, classification and treatment options for polycystic liver diseases. World J Gastroenterol 2013;19:5775–5786

    Article  Google Scholar 

  9. Gabow PA, Johnson AM, Kaehny WD, Manco-Johnson ML, Duley IT, Everson GT. Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease. Hepatology 1990;11:1033–1037

    Article  CAS  Google Scholar 

  10. Kataoka H, Ono K, Mochizuki T, Hanafusa N, Imai E, Hishida A, Nitta K. A Body mass index-based cross-classification approach for the assessment of prognostic factors in chronic kidney disease progression. Kidney Blood Press Res 2019;44:362–383

    Article  CAS  Google Scholar 

  11. Cornec-Le Gall E, Torres VE, Harris PC. Genetic complexity of autosomal dominant polycystic kidney and liver diseases. J Am Soc Nephrol 2018;29:13–23

    Article  Google Scholar 

  12. Chebib FT, Jung Y, Heyer CM, Irazabal MV, Hogan MC, Harris PC, Torres VE, El-Zoghby ZM. Effect of genotype on the severity and volume progression of polycystic liver disease in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2016;31:952–960

    Article  CAS  Google Scholar 

  13. Kataoka H, Fukuoka H, Makabe S, Yoshida R, Teraoka A, Ushio Y, Akihisa T, Manabe S, Sato M, Mitobe M, Tsuchiya K, Nitta K, Mochizuki T. Prediction of renal prognosis in patients with autosomal dominant polycystic kidney disease using pkd1/pkd2 mutations. J Clin Med 2020;9:146

    Article  CAS  Google Scholar 

  14. Mochizuki T, Teraoka A, Akagawa H, Makabe S, Akihisa T, Sato M, Kataoka H, Mitobe M, Furukawa T, Tsuchiya K, Nitta K. Mutation analyses by next-generation sequencing and multiplex ligation-dependent probe amplification in Japanese autosomal dominant polycystic kidney disease patients. Clin Exp Nephrol 2019;23:1022–1030

    Article  CAS  Google Scholar 

  15. Drenth JP, Chrispijn M, Nagorney DM, Kamath PS, Torres VE. Medical and surgical treatment options for polycystic liver disease. Hepatology 2010;52:2223–2230

    Article  Google Scholar 

  16. Muto S, Ando M, Nishio S, Hanaoka K, Ubara Y, Narita I, Kamura K, Mochizuki T, Tsuchiya K, Tsuruya K, Horie S. The relationship between liver cyst volume and QOL in Japanese ADPKD patients. Clin Exp Nephrol 2020;24:314–322

    Article  CAS  Google Scholar 

  17. Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable in logistic and Cox regression. Am J Epidemiol 2007;165:710–718

    Article  Google Scholar 

  18. Hoevenaren IA, Wester R, Schrier RW, McFann K, Doctor RB, Drenth JP, Everson GT. Polycystic liver: clinical characteristics of patients with isolated polycystic liver disease compared with patients with polycystic liver and autosomal dominant polycystic kidney disease. Liver Int 2008;28:264–270

    Article  Google Scholar 

  19. Gigot JF, Jadoul P, Que F, Van Beers BE, Etienne J, Horsmans Y, Collard A, Geubel A, Pringot J, Kestens PJ. Adult polycystic liver disease: is fenestration the most adequate operation for long-term management? Ann Surg 1997;225:286–294

    Article  CAS  Google Scholar 

  20. Torres VE, Chapman AB, Perrone RD, Bae KT, Abebe KZ, Bost JE, Miskulin DC, Steinman TI, Braun WE, Winklhofer FT, Hogan MC, Oskoui FR, Kelleher C, Masoumi A, Glockner J, Halin NJ, Martin DR, Remer E, Patel N, Pedrosa I, Wetzel LH, Thompson PA, Miller JP, Meyers CM, Schrier RW. Analysis of baseline parameters in the HALT polycystic kidney disease trials. Kidney Int 2012;81:577–585

    Article  CAS  Google Scholar 

  21. Hogan MC, Abebe K, Torres VE, Chapman AB, Bae KT, Tao C, Sun H, Perrone RD, Steinman TI, Braun W, Winklhofer FT, Miskulin DC, Rahbari-Oskoui F, Brosnahan G, Masoumi A, Karpov IO, Spillane S, Flessner M, Moore CG, Schrier RW. Liver involvement in early autosomal-dominant polycystic kidney disease. Clin Gastroenterol Hepatol 2015;13(155–164):e156

    Google Scholar 

  22. Kataoka H, Ohara M, Honda K, Mochizuki T, Nitta K. Maximal glomerular diameter as a 10-year prognostic indicator for IgA nephropathy. Nephrol Dial Transplant 2011;26:3937–3943

    Article  Google Scholar 

  23. Cornec-Le Gall E, Audrezet MP, Chen JM, Hourmant M, Morin MP, Perrichot R, Charasse C, Whebe B, Renaudineau E, Jousset P, Guillodo MP, Grall-Jezequel A, Saliou P, Ferec C, Le Meur Y. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol 2013;24:1006–1013

    Article  Google Scholar 

  24. Rossetti S, Burton S, Strmecki L, Pond GR, San Millan JL, Zerres K, Barratt TM, Ozen S, Torres VE, Bergstralh EJ, Winearls CG, Harris PC. The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with the severity of renal disease. J Am Soc Nephrol 2002;13:1230–1237

    Article  CAS  Google Scholar 

  25. Hopp K, Ward CJ, Hommerding CJ, Nasr SH, Tuan HF, Gainullin VG, Rossetti S, Torres VE, Harris PC. Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity. J Clin Invest 2012;122:4257–4273

    Article  CAS  Google Scholar 

  26. Masyuk AI, Gradilone SA, LaRusso NF. Calcium signaling in cilia and ciliary-mediated intracellular calcium signaling: are they independent or coordinated molecular events? Hepatology 2014;60:1783–1785.

    Article  CAS  Google Scholar 

  27. Masyuk AI, Masyuk TV, Splinter PL, Huang BQ, Stroope AJ, LaRusso NF. Cholangiocyte cilia detect changes in luminal fluid flow and transmit them into intracellular Ca2+ and cAMP signaling. Gastroenterology 2006;131:911–920

    Article  CAS  Google Scholar 

  28. Alvaro D, Onori P, Alpini G, Franchitto A, Jefferson DM, Torrice A, Cardinale V, Stefanelli F, Mancino MG, Strazzabosco M, Angelico M, Attili A, Gaudio E. Morphological and functional features of hepatic cyst epithelium in autosomal dominant polycystic kidney disease. Am J Pathol 2008;172:321–332

    Article  CAS  Google Scholar 

  29. Lu W, Shen X, Pavlova A, Lakkis M, Ward CJ, Pritchard L, Harris PC, Genest DR, Perez-Atayde AR, Zhou J. Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects. Hum Mol Genet 2001;10:2385–2396

    Article  CAS  Google Scholar 

  30. Bergmann C, Guay-Woodford LM, Harris PC, Horie S, Peters DJM, Torres VE. Polycystic kidney disease. Nat Rev Dis Primers 2018;4:50

    Article  Google Scholar 

Download references

Funding

This study was supported in part by Japan Society for the Promotion of Science (KAKENHI Grant Number JP 15K09279) and by a Grant-in-Aid for Intractable Renal Diseases Research, Research on rare and intractable diseases, Health and Labor Sciences Research Grants from the Ministry of Health, Labor and Welfare of Japan.

Author information

Authors and Affiliations

  1. Department of Nephrology, Tokyo Women’s Medical University, -1 Kawada-cho, Shinjuku-ku, Tokyo, 162-866, Japan

    Hiroshi Kataoka, Saki Watanabe, Masayo Sato, Shun Manabe, Shiho Makabe, Taro Akihisa, Yusuke Ushio, Naomi Iwasa, Rie Yoshida, Kosaku Nitta & Toshio Mochizuki

  2. Clinical Research Division for Polycystic Kidney Disease, Department of Nephrology, Tokyo Women’s Medical University, Tokyo, 162-866, Japan

    Hiroshi Kataoka & Toshio Mochizuki

  3. Department of Blood Purification, Tokyo Women’s Medical University, Tokyo, 162-866, Japan

    Ken Tsuchiya

Authors
  1. Hiroshi Kataoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Saki Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masayo Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shun Manabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shiho Makabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Taro Akihisa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yusuke Ushio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Naomi Iwasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rie Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ken Tsuchiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kosaku Nitta
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Toshio Mochizuki
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: HK, and TM; data curation: SW, HK, NI, RY, and TM; formal analysis: HK; writing—original draft: HK; validation: HK, MS, SM (Shun Manabe), SM (Shiho Makabe), TA, YU, and TM; supervision: TM, KT, and KN. All authors contributed important intellectual content during manuscript drafting or revision and accept personal accountability for their contributions, and agree to ensure that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. All authors had access to the study data and reviewed and approved the final manuscript.

Corresponding author

Correspondence to Toshio Mochizuki.

Ethics declarations

Conflicts of interest

Toshio Mochizuki and Ken Tsuchiya received travel fees and honoraria for lectures from Otsuka Pharmaceutical Co. Toshio Mochizuki and Hiroshi Kataoka belong to an endowed department sponsored by Otsuka Pharmaceutical Co., Chugai Pharmaceutical Co., Kyowa Hakko Kirin Co., and JMS Co.

Ethics approval

The study was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2008 and approved by the Research Ethics Committee of Tokyo Women’s Medical University (No. 196B).

Animal Research (Ethics)

Not applicable.

Clinical Trials Registration

Not applicable.

Informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study.

Consent to participate

Informed consent was obtained from all patients to participate in the study.

Consent for publication

Informed consent was obtained from all patients to be included in this manuscript.

Availability of data and material

The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 358 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kataoka, H., Watanabe, S., Sato, M. et al. Predicting liver cyst severity by mutations in patients with autosomal-dominant polycystic kidney disease. Hepatol Int 15, 791–803 (2021). https://doi.org/10.1007/s12072-021-10176-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-021-10176-9

Keywords

Search

Navigation